Secondary Hyperparathyroidism Vitamin D Metabolism …€¦ · – Neurologic system –...

Joslin Diabetes CenterAdvances in Diabetes and Thyroid Disease 20132° Hyperparathyroidism and Vitamin D Metabolism

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Secondary Hyperparathyroidism and Vitamin D Metabolism

Alan Malabanan, MD, FACE

Assistant Professor of Medicine

Harvard Medical School

Disclosure

• AbbVie (equity): Calcijex, Zemplar

Case

52 yo M with DM, ESRD tx

HPI: diarrhea, back pain

MEDS: prednisone, mycophenolate, belatacept, calcitriol, cinacalcet, vitamin D2, cholestyramine, furosemide, insulin, metoprolol, omeprazole, niacin, CaCO3, magnesium

LABS:

PTH 1081 (10‐65)

Ca 7.8 (8.4‐10.3)

Alb 4.4 (3.5‐4.5)

P 1.8 (2.7‐4.5)

Mg 1.0 (1.6‐2.6)

Alk Phos 493 (40‐130)

25OHD 9 (20‐100)

BMD: FN T‐score ‐2.3

1/3 radius T‐score ‐3.8

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Objectives

• Outline the role of PTH in calcium and phosphate homeostasis.

• Define secondary hyperparathyroidism.

• Identify various disease states and medications that increase PTH.

• State the IOM and Endocrine Society guidelines for vitamin D intake.

[Ca+2]

[PO4]

[Mg+2]

[aa]

Serum Calcium’s Role

• Neuromuscular function

– Neurologic system

– Cardiac/skeletal muscle

– Gastrointestinal function

• Secondary messenger

– Endocrine system

• Structural function

– Skeletal system

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Calcium Homeostasis = Life

High intracellular calcium . . .

• Causes organellar damage.

• Causes aggregation of amino and nucleic acids.

• Affects the integrity of lipid membranes

• Precipitates phosphates (needed for energy, i.e. ATP)

JK Jaiswal, J. Biosci., 26: 357–363, 2001.

Case RM et al. Cell Calcium 42:345-350, 2007.

Secondary hyperparathyroidism is a physiologic and compensatory

increase in parathyroid hormone to maintain serum ionized calcium.

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1,25 OH D

Dietary Ca

PTH

Bone Ca

PTH

Urine Ca

↑ PTH Assoc with Health Problems

• Low bone mass and fracture (Chapuy, 2002)

• Hypertension (Jorde, 2000; Taylor, 2008)

• Coronary artery disease (Kamycheva, 2004)

• Congestive heart failure (Sugimoto, 2009)

• Cardiovascular mortality (Hagstrom, 2009)

• Hospitalization (Premaor, 2009)

Why Check a PTH?

• Increased calcium.

• Decreased calcium.

• Decreased phosphate.

• Chronic kidney disease. (Stage 3 and higher)

• Evaluation of osteoporosis.* (Tannenbaum, 2002).

* Most experts are not recommending routine use of PTH in evaluation of osteoporosis in primary care.

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Tannenbaum C et al, JCEM 87(10):4431–4437, 2002

Determinants of ↑PTH

• Calcium intake, vitamin D status (Saleh, 2005)

• Renal failure

• ↑ BMI (27‐29 v 21‐22) (Paik, 2010)

• ↑ age, ↑ uric acid, ↓ vitamin A, Non‐smoking (Paik, 2011)

• Circadian rhythm (Calvo, 1991)

• Phosphorus, Bisphosphonate (Vasikaran, 2001), Furosemide (Stein, 1996), Imatinib (Grey, 2006), Denosumab (Lewiecki, 2007), ?PPI (Subbiah, 2002; Epstein, 2006)

• Hypercalciuria (Misael da Silva, 2002)

Mod from J.‐C. Souberbielle et al. / Clinica Chimica Acta 366 (2006) 81– 89

Factors affecting Ca+2 excretion

• Electrolytes– Sodium

– Calcium

– Phosphate

• Protons

• Hormones– PTH/PTHrP

– 1,25 (OH)2 D

– Calcitonin

• Drugs– Thiazides

– Loop diuretics

– Cyclosporin A

– ?Caffeine

• Genetic mutations– CaSR mutations

– Cl‐ channel mutations

– TALH mutations

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Causes of ↓ intestinal Ca absorption

• Very low dietary calcium intake

• Dec 1,25‐dihydroxyvitamin D

• Vitamin D deficiency

• VDDR Type I

• Chronic renal insufficiency

• Hypoparathyroidism

• Aging

• Glucocorticoid excess

• Thyroid hormone excess

• Intestinal malabsorption

• Celiac disease

• Anticonvulsant therapy

• Gastrectomy

• PPI Therapy

IOM Calcium & Vitamin D RDA 2010

AGE CALCIUM VITAMIN D

19‐30 y 1000 mg 600 IU

31‐50 y 1000 mg 600 IU

51‐70 y1000 mg M1200 mg F

600 IU

> 70 y 1200 mg 800 IU

For Estimate of Dietary Calcium Intake, go to http://bestbonesforever.gov/best_foods/calculator.cfm

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Uremic Hyperparathyroidism

• Hyperphosphatemia

– Increased FGF‐23/Increased PTH

– Decreased 1,25‐dihydroxyvitamin D

• Decreased 1‐α‐hydroxylase

• Increased PTH resistance

Assessing High PTH – 1st Thoughts

• What is the calcium?

• Why was it checked?

• Lab error and artifact.

• Fasting vs. Non‐fasting.

• Consider medication effects.

High PTH

Check CaPrimary HPT

1000‐1200 mg Ca600‐800 IU D

Enough Ca &D?

Check 24 h U Ca

Hypercalciuria

Normocalcemic HPT?

Check 25OHD

HIGH

LOW, NL

NO

YES

LOW HIGH

NL

For Patients with NormalRenal Function

LOWVit D

Deficiency

MalabsorptionMed Effect

NL

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Treatment Principles

• Correct the underlying problem.– Increase calcium supply.

• Adequate calcium intake (citrate vs carbonate)• Correct malabsorption (i.e. celiac disease)• Vitamin D2, Vitamin D3, calcitriol• Correct hypomagnesemia.• Discontinue offending medications, if possible.

– Decrease calcium losses.• Chlorthalidone, HCTZ, amiloride.

– DO NOT USE CINACALCET FOR THESE PATIENTS.

• For Renal insufficiency.– Phosphate binders, cinacalcet, calcitriol, paracalcitol, doxercalciferol, surgery*.

From Malabanan et al, Lancet 1998.

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2 Inflection Points: 12 and 28 ng/ml

Durazo‐Arvizu et al. J. Nutr. 140: 595–599, 2010.

Classification of clinical vitamin D status.

Binkley N et al. JCEM 2008;93:1804-1808

©2008 by Endocrine Society

Treatment of Vitamin D Deficiency

• Suggest for those on anticonvulsants, glucocorticoids, antifungals, and medications for AIDS be given 2‐3X the age recommended daily intake.

• Suggest for adults, 50000 IU weekly x 8 or 6000 IU daily x 8 wk, then 1500‐2000 IU/d maintenance.

• In obese, malabsorbers and those on meds affecting vit D metabolism, suggest 6000‐10000 IU daily x 8 wk, then 3000‐6000 IU/d.

• In granulomatous disease, use 25OHD of 20 ng/ml and monitor for ↑ SCa and Uca.

From: Endocrine Society Guidelines, 2011

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Vitamin D regimens and 25OHD

Amount/Type Dosing % > 30 ng/ml

800 IU D3 Daily in winter 80%

50000 IU D2 Weekly x 4 then monthly x 5

38%

50000 IU D2 Monthly x 6 42%

50000 IU D2 3x weekly x 6 82%

50000 IU D2 Weekly x 8 13-60%

ML Nelson et al, J. Nutr. 139: 540–546, 2009.

KJ Pepper et al, Endocr Pract. 15:95,2009.

Time to Normalization of PTH (TNP) inAfter Vitamin D Repletion

• Retrospective study, n= 40

• Mean age = 64 y, 55% female, 64% Afr Am

• Mean calcium 9.1, 25OHD 13, PTH 106.1,

Cr 1.5

• Mean TNP was 48.3 weeks, median 36.0 weeks

• 75% at 64.5 weeks 95% at 162.9 weeks

• No relationship between TNP and PTH/25OHD

Shoenberger J, Fogg, Fogelfeld. OR31‐3 ENDO 2013

Fasting urinary calcium:creatinine ratio (top left), serum 1,25-dihydroxyvitamin D levels (bottom left), lumbar spine bone density (top right), and femoral neck bone density (bottom

right) in five hypercalciuric men with osteoporosis before (black squares) ...

Adams J S et al. Ann Intern Med 1999;130:658-660

©1999 by American College of Physicians

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Back to the Case

52 yo M with DM, ESRD tx

HPI: diarrhea, back pain

MEDS: prednisone, mycophenolate, belatacept, calcitriol, cinacalcet, vitamin D2, cholestyramine, furosemide, insulin, metoprolol, omeprazole, niacin, CaCO3, magnesium

LABS:

PTH 1081 (10‐65)

Ca 7.8 (8.4‐10.3)

Alb 4.4 (3.5‐4.5)

P 1.8 (2.7‐4.5)

Mg 1.0 (1.6‐2.6)

Alk Phos 493 (40‐130)

25OHD 9 (20‐100)

BMD: FN T‐score ‐2.3

1/3 radius T‐score ‐3.8

Case Follow‐up

• Cinacalcet stopped.

• Magnesium and vitamin D replaced.

• Diarrhea treated.

• Calcitriol increased.

• PTH drops initially to 154 and then 300s

Summary.

• Secondary hyperparathyroidism is compensatory and the underlying problem needs to be identified.

• Persistent hyperparathyroidism may lead to excessive bone loss and other health problems.

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Thank you for your attention!

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